ELN Recommendations on treatment choice and response. Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy

ELN Recommendations on treatment choice and response Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy

ELN 2013 Response to Front-line Treatment Baseline 3 months 6 months OPTIMAL WARNING FAILURE Ph+ 35% BCR-ABL 10% Ph+ 0% BCR-ABL 1% -High risk, -CCA/Ph+ (Major route) Ph+ 36-95% Ph+ 1-35% BCR-ABL 1-10% 12 months BCR-ABL 0.1% BCR-ABL > 0.1-1 % No CHR Ph+ > 95% Ph+ > 35% Ph+ > 0% BCR-ABL > 1% Then BCR-ABL 0.1% BCR-ABL 0.1-1% BCR-ABL > 1% Baccarani et al, Blood 2013; 122: 885-892.

2 nd Generation TKIs in Early CP Outcome and Responses By 5 Years ENESTnd 1 Dasision 2 Treatment Nilotinib Imatinib Imatinib Dasatinib Patient N. 282 283 260 259 5-year PFS & 96.5% 94.7% 85.5% 85.4% 5-year OS^ 93.6% 91.6% 89.6% 90.9% MMR 77% 60% 64% 76% MR 4.5 54% 31% 33% 42% Note: Data from different studies, please interpret with care. & ENESTnd: death from any cause or progression to AP/BC. DASISION: doubling of WBC count, loss of CHR, increase in Ph-positive metaphases to >35%, transformation, or death from any cause ^ ENESTnd Including events occurring on core or extension treatment or during f/u after treatment discontinuation; DASISION Total n. of deaths on-study treatment and in follow-up after discontinuation of randomized treatment. 1 Hughes et al., EHA 2014 Abstract S677 2 Cortes J. et al. ESH, icmlf 2104

2016, the weight of the choice of 1 st line Treatment Patient Risk, comorbidities Personal Expectations Education, compliance Advocacies Drugs Efficacy and time to response Side Effects / QOL Long term safety Costs ENDPOINTS Physician Personal Experience Experience

CML, conceptual model of progression chronic accelerated blast BCR-ABL Instability Proliferation -or?- Point mutations Chromosomal s Differentiation Cell cycle Apoptosis 0 Index of progression 1.0? Normal Chronic Blast Radich et al., PS 2006

ENESTnd: Cumulative Incidence of MMR Cumulative incidence of MMR, % 100 90 80 70 60 50 40 30 20 10 Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) By 1 Year 55%; P <.0001 * Δ 24% to 28% 27% 51%; P <.0001 * By 5 Years 77%; P <.0001 * 77%; P <.0001 * 0 0 6 12 18 24 30 36 42 48 54 60 Months since randomization ** By 6 Years 79%; P <.0001 * 77%; P <.0001 * Δ 16% to 18% 66 72 78 Rates of MMR by 6 years remained higher in the nilotinib arms than in the imatinib arm (Figure 2) Nearly all patients still on core treatment at the data cutoff had achieved MMR; in each arm, 4 patients who had not achieved MMR remained on core treatment at the data cutoff (among these 12 patients, 5 had atypical transcripts at baseline and 7 had a best response of BCR-ABL IS >0.1% to 1%) 60% Δ 17% * P values are nominal. ** For each arm, the curve stops at the latest time point at which a patient first achieved MMR. 61% Larson RA, et al. ASH 2014. Abstract 4541.

Sokal High-Risk Patients Had Significantly Worse Responses on Imatinib 100 80 EFS (%) 60 40 20 0 Sokal risk score n PFS at EFS at 60 months 1 54 months 2 Low 201 97% 90% Intermediate 111 92% 83% High 71 83% 71% P<0.001 P<0.001 0 12 24 36 48 60 Months Data from the IRIS trial 1. Hochhaus A, et al. Leukemia 2009;23:1054 61 2. Baccarani M. Relative Risk (Sokal & Hasford) Available at: http://www.leukemia-net.org/content/leukemias/cml/research/research/

Progression to AP/BC on Study a According to Sokal Risk Score Patients With Progression to AP/BC, n 12 10 8 6 4 2 0 Low Sokal Risk 1 1 0 Intermediate Sokal Risk 2 n = 103 103 104 101 100 101 78 78 78 1 All 3 progressions to AP/BC on study reported since the 4-year analysis occurred in patients with high Sokal risk scores at baseline; all 3 patients also had BCR-ABL IS > 10% at 3 months All progressions in patients with low/intermediate Sokal risk scores occurred during the first 2 years on study a Progression to AP/BC or death due to advanced CML on core treatment or during follow-up after discontinuation of core treatment. 10 High Sokal Risk 1.0% 1.0% 2.0% 1.0% 9.9% 9.0% 5.1% 14.1% 7 4 11 New events reported since the 4-year analysis Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Data cutoff: September 30, 2013

Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial Hochhaus et al, Leukemia 2016

Defining Molecular Response Requirements for Potential Treatment Discontinuation 1 Response at Time of Treatment Discontinuation Patients with Molecular Cytogenetic Relapse, % CCyR 2 100% MMR 3 100% MMR, CCyR, MCyR 4 100% CMR for 2 years on imatinib 5-8 ~30% 65% CCyR, complete cytogenetic response; CMR, complete molecular response; MCyR, major cytogenetic response; MMR, major molecular response. 1. Milojkovic D et al. Blood. 2011;118(21): abstract 605; 2. Goh HG, et al. Leuk Lymphoma. 2009;50(6):944-951; 3. Koskenvesa P, et al. Blood. 2008;112(11):738. Abstract 2121; 4. Kuwabara A, et al. Blood. 2010;116(6):1014-1016; 5. Mahon FX, et al. Blood. 2011;118(21): abstract 603; 6. Rousselot P, et al. Blood. 2011;118(21): abstract 3781; 7. Goh HG, et al. Blood. 2011;118(21): abstract 2763; 8. Matsuki E, et al. Blood. 2011;118(21): abstract 3765.

CML Potential Molecular Cures Imatinib (%) Nilo/Dasa (1,2) (%) MR 4.5 at 5 yr 40 60 70 CMR 2 3 yr 30 50+ Molecular cures 15 25 30 1 Hughes et al., EHA 2014 Abstract S677 2 Cortes J. et al. ESH, icmlf 2104

ELN Recommendations on treatment choice and response Gianantonio Rosti, MD, Department of Hematology, University of Bologna, Italy